Skeletal unloading induced by disuse or immobilization causes a decrease in bone mass and strength. We investigated the relationship between whole-body vibration (WBV) and resistance exercise (RE) in preventing bone loss induced by 8-week hindlimb unloading in young male rats. Sixty male Wistar rats were assigned randomly to 6 groups: age-matched control group (CON, n = 10), hindlimb unloading group (HU, n = 10), hindlimb unloading + standing group (HU + ST, n = 10), hindlimb unloading + WBV group (HU + WBV, n = 10), hindlimb unloading + RE group (HU + RE, n = 10) and hindlimb unloading + WBV + RE group (HU + WBV + RE, n = 10). After 8-week hindlimb unloading, micro-CT scanning and three-point bending test were performed in the femur. Sera were collected for analysis of bone formation and resorption markers. Compared with HU group, WBV, RE and the combination of WBV and RE (WBV + RE) significantly improved (P < 0.01) one repetition maximum (1RM) (expressed as the percentage change from baseline, HU: -23%, HU + WBV: 21%, HU + RE: 48%, HU + WBV + RE: 51%), and maintained (P < 0.05) cancellous volumetric bone mineral density (vBMD) and trabecular structure. No difference of cortical vBMD was found among all groups (P > 0.05). WBV had no effects on biomechanical properties of the femur diaphysis (P > 0.05). RE and WBV + RE significantly increased maximum load and cross-sectional moment of inertia of the femur diaphysis in hindlimb unloading rats (P < 0.05). There was an interaction between WBV and RE in improving cancellous bone. These results demonstrate that WBV and RE interactively maintain cancellous structure and vBMD, and independently partially mitigate the reduction of bone strength in long-term hindlimb unloading rats.